Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism

Abstract

Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action.

Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE.

Methods: Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke.

Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, P-value=8.08×10(-16) ) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40.

Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.

Figure 1

Manhattan plot of association results between VTE and candidate gene SNPs by chromosome. The x-axis displays the chromosomes and the y-axis displays the −log10 p-values. The horizontal line represents the −log10 of the Bonferroni corrected p-value (−log[4.0E-06] = 5.40). The significant results (Bonferroni corrected p-value < 4.0E-06) are labeled by gene name and SNP rs number. The r² value between the two F5 SNPs is 0. The r² values between the ABO SNPs are as depicted in details in Figure 2.

Figure 2

Haploview linkage disequilibrium plot of ABO SNPs (n=17). Blocks represent SNPs in high linkage disequilibrium. Greater color intensity corresponds to a higher level of linkage disequilibrium given by D’. The value inside each cell represents linkage disequilibrium given by r². Blue rectangles outline the ABO blood group SNPs (homozygous deletion on rs8176719 determines O blood type). Green rectangles outline ABO SNPs significantly associated with VTE. ABO SNPs from HapMap build 36.3 are displayed above the Haploview plot.